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R. A. Lahti

Bio: R. A. Lahti is an academic researcher from Pfizer. The author has contributed to research in topics: Pharmacokinetics & Placebo. The author has an hindex of 1, co-authored 1 publications receiving 37 citations.

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TL;DR: This study suggests that (−)-3PPP/preclamol is a safe drug for study in the treatment of schizophrenia and may have antipsychotic efficacy.
Abstract: The dopamine (DA) autoreceptor agonist (−)-3PPP (preclamol) was tested in male schizophrenic volunteers for safety. The drug was administered intramuscularly in a single rising dose design, crossed with a similar “rising dose” placebo period; all evaluations and raters were blind to drug or placebo administration. Pharmacokinetic, endocrine, safety, and mental status outcome measures were completed before and after each single dose of drug or placebo. Pharmacokinetic analysis showed blood levels between 200–500 pmoles/ml after the intramuscular drug doses of 30–40 mg. Drug half life is 2–2.5 hrs. Growth hormone (GH) levels were elevated in a linear fashion to the 30 mg dose; whereafter, the drug failed to affect GH at all. All safety evaluations were negative, including any untoward effects on the major organ systems. After single dose drug administration, evidence of antipsychotic action occurred in two of the four subjects. This study suggests that (−)-3PPP/preclamol is a safe drug for study in the treatment of schizophrenia and may have antipsychotic efficacy.

37 citations


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TL;DR: In this article, a critical review with 430 references covers the results obtained in the period January 2009 to February 2013 in the area of the transition metal-catalyzed direct inter- and intramolecular (hetero)arylation reactions of heteroarenes containing one heteroatom.
Abstract: In recent years, transition metal-catalyzed direct (hetero)arylation reactions of heteroarenes with (hetero)aryl halides and pseudohalides have received significant attention as eco-friendly and economic alternatives to classical methods for the construction of heteroaryl-(hetero)aryl CC bonds by transition metal-catalyzed cross-couplings involving the use of stoichiometric amounts of organometallic reagents. This critical review with 430 references covers the results obtained in the period January 2009 to February 2013 in the area of the transition metal-catalyzed direct inter- and intramolecular (hetero)arylation reactions of heteroarenes containing one heteroatom. Particular attention has been given to illustrate chemo- and site selectivity aspects of these reactions as well applications of these CC bond forming reactions in the synthesis of pharmaceutically relevant compounds, natural products and their analogues and precursors. The most recent advancements into the mechanism(s) of these reactions have also been briefly reported.

365 citations

Journal ArticleDOI
TL;DR: This review discusses salient distinctions predominantly between prototypic atypical and typical antipsychotic drugs such as clozapine and haloperidol, respectively.
Abstract: Various criteria used to define atypical antipsychotic drugs include: 1) decrease, or absence, of the capacity to cause acute extrapyramidal motor side effects (acute EPSE) and tardive dyskinesia (TD); 2) increased therapeutic efficacy reflected by improvement in positive, negative, or cognitive symptoms; 3) and a decrease, or absence, of the capacity to increase prolactin levels. The pharmacologic basis of atypical antipsychotic drug activity has been the target of intensive study since the significance of clozapine was first appreciated. Three notions have been utilized conceptually to explain the distinction between atypical versus typical antipsychotic drugs: 1) dose-response separation between particular pharmacologic functions; 2) anatomic specificity of particular pharmacologic activities; 3) neurotransmitter receptor interactions and pharmacodynamics. These conceptual bases are not mutually exclusive, and the demonstration of limbic versus extrapyramidal motor functional selectivity is apparent within each arbitrary theoretical base. This review discusses salient distinctions predominantly between prototypic atypical and typical antipsychotic drugs such as clozapine and haloperidol, respectively. In addition, areas of common function between atypical and typical antipsychotic drug action may also be crucial to our identification of pathophysiological foci of the different dimensions of schizophrenia, including positive symptoms, negative symptoms, and neurocognitive deficits.

309 citations

Journal ArticleDOI
TL;DR: The D(2) functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D( 2) antagonists, as well as those that also bind with modest affinity to 5-HT(2A), and many other neuroreceptors.
Abstract: Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D(2) receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D(2) and 5-HT(2A) antagonists, and those that also bind with modest affinity to D(2), 5-HT(2A), and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D(2) partial agonism or D(2) functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D(2) functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D(2) antagonists.

266 citations

Journal ArticleDOI
TL;DR: It appears that the significant progress that is being made in the molecular understanding of DA receptors will continue to have a tremendous impact in the pharmacological treatment of neuropsychiatric, cardiovascular, and renal diseases.

236 citations

Journal ArticleDOI
02 Nov 2001-Science
TL;DR: This paradigm shift opened up an enormous new perspective in brain research, not least by facilitating the study of brain function by means of chemical tools, which in different ways could modify the chemical signaling between nerve cells.
Abstract: As late as the 1950s, it was assumed that communication between nerve cells in the brain occurred predominantly, if not entirely, by electrical impulses. A decade later, the theory of chemical transmission, which until then had been thought to occur only in the peripheral nervous system, had gained strong entrance for the central nervous system. This paradigm shift opened up an enormous new perspective in brain research, not least by facilitating the study of brain function by means of chemical tools, which in different ways could modify the chemical signaling between nerve cells. Moreover, such tools sometimes turned out to be useful as therapeutic agents. Thus for the first time, a variety of disorders in the central nervous system could be treated effectively.

201 citations